Human FBXL8 Is a Novel E3 Ligase Which Promotes BRCA Metastasis by Stimulating Pro-Tumorigenic Cytokines and Inhibiting Tumor Suppressors
The initiation and progression of breast cancer (BRCA) is associated with inflammation and immune-overactivation, which is critically modulated by the E3 ubiquitin ligase. However, the underlying mechanisms and key factors involved in BRCA formation and disease advancement remains under-explored. By...
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| Format: | Article |
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MDPI AG
2020-08-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/12/8/2210 |
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| author | Shu-Chun Chang Wayne Hsu Emily Chia-Yu Su Chin-Sheng Hung Jeak Ling Ding |
| author_facet | Shu-Chun Chang Wayne Hsu Emily Chia-Yu Su Chin-Sheng Hung Jeak Ling Ding |
| author_sort | Shu-Chun Chang |
| collection | DOAJ |
| description | The initiation and progression of breast cancer (BRCA) is associated with inflammation and immune-overactivation, which is critically modulated by the E3 ubiquitin ligase. However, the underlying mechanisms and key factors involved in BRCA formation and disease advancement remains under-explored. By retrospective studies of BRCA patient tissues; and gene knockdown and gain/loss-of-function studies, we uncovered a novel E3 ligase, FBXL8, in BRCA. A signature expression profile of F-box factors that specifically target and degrade proteins involved in cell death/survival, was identified. FBXL8 emerged as a prominent member of the F-box factors. Ex vivo analysis of 1349 matched BRCA tissues indicated that FBXL8 promotes cell survival and tumorigenesis, and its level escalates with BRCA progression. Knockdown of FBXL8 caused: (i) intrinsic apoptosis, (ii) inhibition of cell migration and invasion, (iii) accumulation of two tumor-suppressors, CCND2 and IRF5, and (iv) downregulation of cancer-promoting cytokines/chemokines; all of which curtailed the tumor microenvironment and displayed potential to suppress cancer progression. Co-IP study suggests that two tumor-suppressors, CCND2 and IRF5 are part of the immune-complex of FBXL8. The protein levels of CCND2 and IRF5 inversely correlated with FBXL8 expression, implying that FBXL8 E3 ligase was associated with the degradation of CCND2 and IRF5. Altogether, we propose the exploitation of the ubiquitin signaling axis of FBXL8-CCND2-IRF5 for anti-cancer strategies and potential therapeutics. |
| first_indexed | 2024-03-10T17:48:41Z |
| format | Article |
| id | doaj.art-2c7abf3b479340b28c1a11e49f50d063 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-10T17:48:41Z |
| publishDate | 2020-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-2c7abf3b479340b28c1a11e49f50d0632023-11-20T09:25:26ZengMDPI AGCancers2072-66942020-08-01128221010.3390/cancers12082210Human FBXL8 Is a Novel E3 Ligase Which Promotes BRCA Metastasis by Stimulating Pro-Tumorigenic Cytokines and Inhibiting Tumor SuppressorsShu-Chun Chang0Wayne Hsu1Emily Chia-Yu Su2Chin-Sheng Hung3Jeak Ling Ding4The Ph.D. Program for Translational Medicine, College for Medical Science and Technology, Taipei Medical University, Taipei 110, TaiwanDivision of Acute Care Surgery, Department of Surgery, Taipei Medical University Hospital, Taipei 110, TaiwanGraduate Institute of Biomedical Informatics, College of Medical Science and Technology, Taipei Medical University, Taipei 110, TaiwanDivision of General Surgery, Department of Surgery, Shuang Ho Hospital, Taipei Medical University, Taipei 110, TaiwanDepartment of Biological Sciences, National University of Singapore, Singapore 117543, SingaporeThe initiation and progression of breast cancer (BRCA) is associated with inflammation and immune-overactivation, which is critically modulated by the E3 ubiquitin ligase. However, the underlying mechanisms and key factors involved in BRCA formation and disease advancement remains under-explored. By retrospective studies of BRCA patient tissues; and gene knockdown and gain/loss-of-function studies, we uncovered a novel E3 ligase, FBXL8, in BRCA. A signature expression profile of F-box factors that specifically target and degrade proteins involved in cell death/survival, was identified. FBXL8 emerged as a prominent member of the F-box factors. Ex vivo analysis of 1349 matched BRCA tissues indicated that FBXL8 promotes cell survival and tumorigenesis, and its level escalates with BRCA progression. Knockdown of FBXL8 caused: (i) intrinsic apoptosis, (ii) inhibition of cell migration and invasion, (iii) accumulation of two tumor-suppressors, CCND2 and IRF5, and (iv) downregulation of cancer-promoting cytokines/chemokines; all of which curtailed the tumor microenvironment and displayed potential to suppress cancer progression. Co-IP study suggests that two tumor-suppressors, CCND2 and IRF5 are part of the immune-complex of FBXL8. The protein levels of CCND2 and IRF5 inversely correlated with FBXL8 expression, implying that FBXL8 E3 ligase was associated with the degradation of CCND2 and IRF5. Altogether, we propose the exploitation of the ubiquitin signaling axis of FBXL8-CCND2-IRF5 for anti-cancer strategies and potential therapeutics.https://www.mdpi.com/2072-6694/12/8/2210FBXL8 SCF E3 ubiquitin ligaseCCND2IRF5breast cancer (BRCA) and metastasispro-tumorigenic microenvironment |
| spellingShingle | Shu-Chun Chang Wayne Hsu Emily Chia-Yu Su Chin-Sheng Hung Jeak Ling Ding Human FBXL8 Is a Novel E3 Ligase Which Promotes BRCA Metastasis by Stimulating Pro-Tumorigenic Cytokines and Inhibiting Tumor Suppressors Cancers FBXL8 SCF E3 ubiquitin ligase CCND2 IRF5 breast cancer (BRCA) and metastasis pro-tumorigenic microenvironment |
| title | Human FBXL8 Is a Novel E3 Ligase Which Promotes BRCA Metastasis by Stimulating Pro-Tumorigenic Cytokines and Inhibiting Tumor Suppressors |
| title_full | Human FBXL8 Is a Novel E3 Ligase Which Promotes BRCA Metastasis by Stimulating Pro-Tumorigenic Cytokines and Inhibiting Tumor Suppressors |
| title_fullStr | Human FBXL8 Is a Novel E3 Ligase Which Promotes BRCA Metastasis by Stimulating Pro-Tumorigenic Cytokines and Inhibiting Tumor Suppressors |
| title_full_unstemmed | Human FBXL8 Is a Novel E3 Ligase Which Promotes BRCA Metastasis by Stimulating Pro-Tumorigenic Cytokines and Inhibiting Tumor Suppressors |
| title_short | Human FBXL8 Is a Novel E3 Ligase Which Promotes BRCA Metastasis by Stimulating Pro-Tumorigenic Cytokines and Inhibiting Tumor Suppressors |
| title_sort | human fbxl8 is a novel e3 ligase which promotes brca metastasis by stimulating pro tumorigenic cytokines and inhibiting tumor suppressors |
| topic | FBXL8 SCF E3 ubiquitin ligase CCND2 IRF5 breast cancer (BRCA) and metastasis pro-tumorigenic microenvironment |
| url | https://www.mdpi.com/2072-6694/12/8/2210 |
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